The basic goal of this project has been to understand better the underlying pathogenic mechanisms involved in papilledema, optic atrophy, and glaucoma. The emphasis has been on glaucoma, and essentially is now the exlcusive subject of investigation. The long-term aim is to understand how elevation of intraocular pressure--together with any other factors that might be involved- -destroys axons, causes loss of redistribution of astroglia, and changes the configuration of the lamina cribrosa. The axon damage is the main feature relevant to visual loss. The hope is that by identifying the mechanism of pressure-induced damage and the factors involved we can (1) identify those at risk, in order to guide us when deciding who needs to have their intraocular pressure lowered, and (2) perhaps also to be able to devise rational and effective therapy directed at the optic nerve pathophysiology in place of or in addition to lowering the intraocular pressure. Therapy directed at the pathophysiology is the optic nerve is needed especially when faced with a case in which the optic nerve continues to be damaged despite a normal intraocular pressure ("low tension glaucoma") or in ordinary glaucoma despite the maximal pressure lowering that can be achieved with safe current therapy. It is now proposed specifically to explore the hypothesis that special sensitivity of the optic disc is an indirect consequence of the fact that certain blood components that are retained by the blood-brain-barrier leak into the choroid (which has no such barrier), and from there they diffuse into the optic nerve head, circumventing the barriar of the wall of the optic disc vessels. Vasoconstrictors are among the substances circulating in the blood stream, and they presumably participate in the body's vascular homeostasis by controlling vascular tone in peripheral tissues. They do not affect CNS vessels (where flow is controlled by autoregulation according to local tissue needs), because they are prevented from reaching the muscular walls of the vessels by the tightly joined endothelial cells that contribute the blood- brain-barrier. However, when these circulating vasoconstrictors reach the muscular coat of the optic nerve vessel by diffusing from the choroid, resulting vascular tone may impair the dilation required as an autoregulatory response when the circulating is challenged by elevation of intraocular pressure.